Metabolic rewiring in keratinocytes by miR-31-5p identifies therapeutic intervention for psoriasis.

Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions by increasing glutamine metabolism. In addition, miR-31 expression results in not only secretion of specific metabolites (aspartate and glutamate) but also secretion of immunomodulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31-induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

Combined arm stretch positioning and neuromuscular electrical stimulation during rehabilitation does not improve range of motion, shoulder pain or function in patients after stroke: a randomised trial.

QUESTION: Does static stretch positioning combined with simultaneous neuromuscular electrical stimulation (NMES) in the subacute phase after stroke have beneficial effects on basic arm body functions and activities? DESIGN: Multicentre randomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis. PARTICIPANTS: Forty-six people in the subacute phase after stroke with severe arm motor deficits (initial Fugl-Meyer Assessment arm score ≤ 18). INTERVENTION: In addition to conventional stroke rehabilitation, participants in the experimental group received arm stretch positioning combined with motor amplitude NMES for two 45-minute sessions a day, five days a week, for eight weeks. Control participants received sham arm positioning (ie, no stretch) and sham NMES (ie, transcutaneous electrical nerve stimulation with no motor effect) to the forearm only, at a similar frequency and duration. OUTCOME MEASURES: The primary outcome measures were passive range of arm motion and the presence of pain in the hemiplegic shoulder. Secondary outcome measures were severity of shoulder pain, restrictions in performance of activities of daily living, hypertonia, spasticity, motor control and shoulder subluxation. Outcomes were assessed at baseline, mid-treatment, at the end of the treatment period (8 weeks) and at follow-up (20 weeks). RESULTS: Multilevel regression analysis showed no significant group effects nor significant time × group interactions on any of the passive range of arm motions. The relative risk of shoulder pain in the experimental group was non-significant at 1.44 (95% CI 0.80 to 2.62). CONCLUSION: In people with poor arm motor control in the subacute phase after stroke, static stretch positioning combined with simultaneous NMES has no statistically significant effects on range of motion, shoulder pain, basic arm function, or activities of daily living. TRIAL REGISTRATION: NTR1748.